Targeting cancer stem cells with CAR-based immunotherapy: biology, evidence, and future directions

Cancer stem cells (CSCs) are pivotal in tumor initiation, progression, and relapse, underscoring the need for targeted therapies to achieve lasting responses. This review delves into CSC biology, highlighting their tumor-initiating potential demonstrated through limiting dilution assays and their role in resistance to therapies. Although successful CAR therapies, such as anti-CD19 CAR T-cells, can induce complete responses without directly targeting CSCs, CAR strategies focusing on CSCs may offer promising avenues to prevent recurrence. We assess CAR therapies targeting CSC-specific antigens, including CD133 and GD2, in preclinical and clinical contexts, emphasizing their effectiveness against glioblastoma, breast cancer, and other malignancies. Nevertheless, challenges such as marker specificity and suppression by the tumor microenvironment (TME) persist. Future strategies, which may include dual-targeting and AI-driven marker discovery, aim to improve CSC elimination and advance personalized cancer immunotherapy.